The overall objective is to determine the potential clinical usefulness of aspirin or naproxen and omeprazole administered together for colorectal cancer (CRC) prevention in preclinical models. In spite of extensive preclinical data on the efficacy of aspirin, naproxen and, to certain extent, omeprazole on CRC chemoprevention, there are significant concerns in translating preclinical doses to human clinical trials. Another concern is that long-term NSAIDs use is associated with gastrointestinal (GI) side-effects, thus limiting the application in individuals at high-risk for CRC. The hypothesis is that combining aspirin or naproxen with omeprazole will provide a safer approach to eliminate the GI toxicity and improve the chemopreventive efficacy of aspirin or naproxen. Thus, it is imperative to develop clinically relevant doses of aspirin or naproxen in combination with omeprazole for CRC prevention in high-risk individuals.